Dystonia and cerebellar atrophy in Cacna1a null mice lacking P/Q calcium channel activity

Abstract

P/Q-type voltage-dependent calcium channel CACNA1A mutations cause dominantly inherited migraine, episodic ataxia, and cerebellar atrophy in humans and cause recessively inherited ataxia, episodic dyskinesia, cerebellar atrophy, and absence epilepsy in mice. The basis of these species differences and the disease mechanism(s) are not understood. To address this question and to identify required P/Q function in vivo, we created a germline Cacna1a null mutation (designated Cacna1a Fcrtm1) by gene targeting. Null mice develop dystonia and late-onset cerebellar degeneration in a specific pattern. This indicates a requirement for P/Q function for survival in a subset of cerebellar neurons. Homozygous null mice completely lack P/Q-type channel activity, and they also lack ω-CTx-MVIIC receptors, indicating that a single gene encodes P/Q channel activity. An increase of L- and N-type current densities is detected in P/Qnull granule cells. Heterozygous Cacna1a Fcrtm1/+ mice are phenotypically normal, despite having a 50% reduction in current density, indicating that reduced current density is not itself sufficient to cause the pathophysiology of spontaneous mouse mutants with ataxia and seizures

Evaluation of the 3p21.3 tumour-suppressor gene cluster

“…The homozygous null mice also had an increased frequency of bradycardia, but also a smaller reduction of heart rate in response to isoflurane anaesthesia, suggesting that the sympathetic regulation of cardiac functions is altered in this mouse model (Ivanov et al, 2004). Similarities between the cacna2d2 null mouse and the cacna1a null mouse (Fletcher et al, 2001) suggested to Ivanov et al (2004) that the same channel (that is, the Ca V 2.1 channel that regulates P/Q-type currents) was involved and in support of this the P-type currents are reduced in the Purkinje cells of ducky homozygotes (Barclay et al, 2001). Interestingly, the drug gabapentin which has analgaesic and antiepileptic uses can bind to a2d1 a2d2, but not a2d3 a2d4.…”

Familial Hemiplegic Migraine

“…Deletion of the Ca V 2.1␣ 1 mouse gene leads to severe cerebellar ataxia and dystonia together with selective progressive cerebellar degeneration. 22,23 Different mouse strains with spontaneous Ca V 2.1␣ 1 mutations all suffer from ataxia and exhibit reduced P/Q-type current in Purkinje cells. 24 Moreover, null Ca V 2.1 Ϫ/Ϫ mice and the majority of the spontaneous mutants harboring loss-of-function mutations in Ca V 2.1 show absence seizures.…”

Familial hemiplegic migraine mutations increase Ca 2+ influx through single human Ca V 2.1 channels and decrease maximal Ca V 2.1 current density in neurons

“…In half of the families tested, FHM is caused by missense mutations in CACNA1A (8), the gene encoding the pore-forming ␣ 1 -subunit of Ca V 2.1 (voltage-gated P͞Q-type Ca 2ϩ ) channels (9)(10)(11)(12). Ca V 2.1 channels are located in presynaptic terminals throughout the brain (13) and play a prominent role in controlling neurotransmitter release at most synapses (14).…”

“…Cerebellar granule cells were grown in primary culture from 6-day-old Ca V 2.1␣ 1 Ϫ/Ϫ mice as described (12). Experiments were performed on cells grown from 5 to 7 days in vitro.…”